Description
Description : Apolipoprotein (apo) E4 is the major genetic risk factor for Alzheimer’s disease (AD). ApoE4 has sex-dependent effects,
whereby the risk of developing AD is higher in apoE4-expressing females than males. However, the mechanism underlying
the sex difference, in relation to apoE4, is unknown. Previous findings indicate that apoE4 causes age-dependent
impairments of hilar GABAergic interneurons in female mice, leading to learning and memory deficits. Here, we investigate
whether the detrimental effects of apoE4 on hilar GABAergic interneurons are sex-dependent using apoE knock-in (KI) mice
across different ages. We found that in female apoE-KI mice, there was an age-dependent depletion of hilar GABAergic
interneurons, whereby GAD67- or somatostatin-positive–but not NPY- or parvalbumin-positive–interneuron loss was
exacerbated by apoE4. Loss of these neuronal populations was correlated with the severity of spatial learning deficits at
16 months of age in female apoE4-KI mice: however, this effect was not observed in female apoE3-KI mice. In contrast, we
found an increase in the numbers of hilar GABAergic interneurons with advancing age in male apoE-KI mice, regardless of
apoE genotype. Moreover, male apoE-KI mice showed a consistent ratio of hilar inhibitory GABAergic interneurons to
excitatory mossy cells approximating 1.5 that is independent of apoE genotype and age, whereas female apoE-KI mice
exhibited an age-dependent decrease in this ratio, which was exacerbated by apoE4. Interestingly, there are no apoE
genotype effects on GABAergic interneurons in the CA1 and CA3 subregions of the hippocampus as well as the entorhinal
and auditory cortexes. These findings suggest that the sex-dependent effects of apoE4 on developing AD is in part
attributable to inherent sex-based differences in the numbers of hilar GABAergic interneurons, which is further modulated
by apoE genotype.